University of Minnesota bioethicist Leigh Turner has been threatened with a lawsuit by a stem cell clinic-related business. Threats in this arena come up every so often and as much as they are unpleasant realities, they can also reveal some important aspects of the stem cell arena. Ars Technica reported yesterday that Leigh’s recent paper on stem cell clinics and businesses associated with them with listings of non-FDA approved offerings in Clinicaltrials.gov was the impetus for the threat of a lawsuit and intention of asking for a retraction/correction.

An email to Leigh from Duncan Ross, the president of The Kimera Society (one of several organizations discussed in Leigh’s paper), included the reported litigation threat, which was quoted in Ars this way:

“I encourage you to amend your publication or I am going to bring suit against the institution for defamation or slander. I am going to lobby the journal for the retraction of this publication. I followed the letter of the FDA as it exists at this time and I am not going to have my name disparaged because of your lack of interest in due diligence…You continue to assume I’m being devious in some way and I’ve had enough.”

As someone who not only does stem cell research, but also writes about stem cell research and clinics, this struck me as an important development and I wanted to learn more about it. I asked Leigh for comment on this situation and he sent me his perspective along with his view of the larger context (you can read his full comment here):

“My article accurately states that the Kimera Society registered on ClinicalTrials.gov a pay-to-participate study in which adipose derived stem cells are administered to individuals with Chronic Obstructive Pulmonary Disease. The ClinicalTrials.gov listing does not disclose that study subjects are charged but this information is in the public domain and Duncan Ross, founder of Kimera, acknowledges that study subjects with COPD pay to participate in this study. My article also argues that studies involving administration of autologous adipose-derived stem cells to individuals with COPD appear to require an Investigational New Drug application that has been submitted to the FDA for review and cleared by CBER. In response, Duncan Ross has called for a retraction of my article and threatened that he will sue for libel or defamation if the article is not corrected or retracted.”

For balance I also asked Duncan Ross for a comment on this situation. I thought this was particularly important to do since Leigh and I have published work together, and share some concerns about direct-to-consumer marketing of stem cells. Here’s the comment that Ross emailed me for this piece:

Duncan Ross, Kimera Society

“My issue with Dr. Turner’s approach is this. Even in the case of your one page blog post, you chose to reach out to me to understand what I, personally, hoped to achieve and/or had done to support the publication of the trial. In fact, I had received IRB approval, whereas Dr. Leigh insinuates throughout his publication that no IRB approval is needed for publication on clinicaltrials.gov. By writing these types of sensational articles, without due diligence, he piques the interest of journalists. These journalists write an article based on a DRAFT guidance, not fully understanding what that means. Then in an email back and forth that I have limited time to attend to, I send only the 2015 approval. That get’s printed. In fact I renewed the IRB every year but didn’t care to continue my discussion with Leigh. What you end up with is someone with a non-scientific background, taking all his time to research and call out companies by name, making them look illegal when in fact I have been in contact with the FDA and done what they require AT THIS TIME. I stood up at the scientific meeting, not public, and suggested that there should be some mechanism to regulate stem cell clinics. There is none at this time. I would pursue it myself through my non-profit. SO failing a pathway, and if IRB approval is not good enough for Leigh, he is going to continue to run around half-cocked and telling half truths. If someone, and I suppose it is going to be me, does not highlight his wholly negative approach, then we might end up curtailing the positive clinical outcomes that the pharmaceutical industry is taking note of and working towards. In fact, my research and the direction of my company is wholly focused on exosome therapies now, a discovery that came out of my experience with these types of autologous stem cell therapies.

If you would like a big red box that says “paid trial’ on clinicaltrials.gov then lobby for its inclusion. If you would prefer stem cell clinics NOT get IRB approval, which I doubt you do, then state that to. I don’t see how choosing the only groups actually working through the requirements available to fulfill today is helpful or professional. Why not discuss the warning letters that were issued and how they were based in large part on sterility.”

Overall, there are hundreds of clinics and associated businesses marketing fat stem cell and other kinds of stem cell treatments for any of a whole medical encyclopedia worth of health conditions. Leigh and I reported on this in our paper in Cell Stem Cell last year. In my opinion, Leigh’s overall scholarship in this area is meritorious and has unique, positive impact. Even so, writing about stem cell direct-to-consumer businesses in any form whether it’s an academic paper or blog can be dicey.

In his comment to me, Leigh highlighted the possible impact that litigation threats can have:

“Mr. Ross’ threat is all-too-representative of the responses that emerge from individuals associated with businesses that charge patients for unproven stem cell interventions. When critiqued, they have a habit of attempting to threaten critics and intimidate them into silence. Such threats have a chilling effect on scholarship. In particular, they make academic journals and researchers wary of identifying businesses by name and critiquing specific commercial practices. The threat of litigation has impeded the ability of researchers to conduct research on such business and publish articles that address important ethical, legal, and scientific issues associated with their marketing claims, business practices, and clinical activities.”

However, one of the challenges for potential plaintiffs in such situations is that just the filing or even threat of a suit poses the risk of bringing them a hefty amount of often negative media attention a la “The Streisand Effect”.

Beyond the potential litigation issue, the Ars piece provides helpful background and new quotes from various parties including stem cell clinic leadership. One of the other interesting aspects of the Ars piece was that it got a meatier FDA quote on stem cell clinics than pretty much anything else I’ve seen from the agency in the recent past:

“We recognize that there are a number of clinics operating, which do not register with FDA. Consumers are encouraged to contact FDA and the appropriate state authorities in their jurisdictions to report any potentially illegal or harmful activity related to stem cell based products. We also encourage patients and health care providers to report adverse events associated with cellular therapies to FDA.”

Does this mean the FDA soon will actually do something concrete to bring more clarity and order to the stem cell commercial arena?

I doubt it, at least most likely not any time soon. We’ll see if as indicated in the new FDA Commissioner’s blog post the upcoming policy statements from the agency in September and then in later months might clarify the regulatory path forward for stem cell offerings such as adipose stem cells as well as other big issues such as non-homologous use and minimal manipulation. One of the rare areas of relatively greater agreement amongst many of the various stakeholders involved in or discussing stem cell clinic practices is the desire for more clarity and consistency from the FDA.

Will Kimera follow through and actually file suit against the University of Minnesota or Turner? If history is any guide, such threats almost always do not result in an actual lawsuit, but it’s possible. Regardless, I’d ask you readers a couple more questions: what is this situation telling us about the stem cell commercial arena today, and what risks and considerations are involved in being a public critic of specific commercial or other practices in the life sciences?

It’s definitely not for the faint of heart.

Note: This piece has been updated since its original posting with a few edits to reflect new information that arose in the comment thread including from Kimera’s Duncan Ross that Kimera may be more of a stem cell clinic-associated business (e.g. supplying cells to clinics) rather than a clinic itself.

18 Comments

Duncan Ross: I have 3 questions:
1. Do you use trypsin or another enzyme to dissociate the adipose cells?
2. What is your argument that this is homologous use – are you supplementing existing fat tissue?
3. What is the mechanism of action of fat cells on COPD?

Jeanne:
1. Re your question regarding trypsin (or collagenase) the proper way to stop that reaction is by quenching with serum. In the protocols referred to in the case of Bioheart and Kristin Comella blinding three patients, the cells were spun down rather than the proteinase being quenched. The collagenase detached the lens in the eye. You could use a ficoll gradient if you wanted to avoid a proteinase and obtain a pure buffy coat population, however, improper use of collagenase is not a reason to stop the use of it going forward.
2 and 3. The argument behind the use of fat is that it contains mesenchymal stem cells (MSC). The fat is thrown away in these protocols. The bone marrow also contains MSC. The lungs were recently identified as a site of hematopoiesis in a Nature article. Thus, the lungs are in effect bone marrow, and using cells from bone marrow would be homologous use. Bone marrow further contains regulatory T cells and other anti-inflammatory cells that suppress the inflammation causing COPD. In theory, infusing bone marrow cells i.v. will allow the cells to traffic to the lungs where they would encounter bone marrow markers. One could tolerize inflammatory cells in the lungs to the insult that causes the COPD. The issue with the COPD patients is that they return to smoking or ‘sneak’ a cigarette, confounding the results. Further, MSC secrete anti-inflammatory proteins, such as TGF-B3, that cause Treg induction and thus lower inflammation. That is the mechanism of action, and the use of these growth factors to attain these results is the focus of my work going forward.

Unfortunately bone marrow therapies for COPD is of only marginal benefit (20 patients treated in 2008-9). Fat derived and umbilical cord stem cells are much better. Also these patients have heavy metals, chronic infections and lots of scarring and chronic hypoxia all of which need to be addressed to get some good improvements in these people.

(1) Starting from the bottom, we see a letter from the founder which states:

“We know you have choices when scouring the internet, and beautiful marketing web sites exist, but I was in your position once when evaluating cancer treatments, and there really is no way for the average patient to evaluate these claims. I only ask that you look for the peer-reviewed publications, and then make a decision.”

Under “COPD” we see a lot of (XYZ et al 20##) but the references are not given, neither are there links to the publications, not even to PubMed. Really, how are we to even know what publication Kimera is talking about?

Well, never mind, after all, as Duncan Ross (PhD) explained: “there really is no way for the average patient to evaluate these claims”.

Such condescension beggars credulity. Surely Duncan Ross must understand that about half of the patient population IS ABOVE AVERAGE!

(2) Duncan Ross talks about his publications but I couldn’t find where they were listed on his website. Can you?

(3) Kimera is, apparently, a metaphor for the aviation industry. Or is the aviation industry a metaphor for Kimera?

Just as well it’s a “metaphor” — otherwise the airlines might be joining in the game of legal argy bargy.

I also had a look at the offending Turner publication:https://www.ncbi.nlm.nih.gov/pubmed/28721755
Well, it’s behind a pay wall so I only checked the abstract. The abstract is so packed with ideological assumptions that I’m inclined to think that Mr Turner, like Mr Ross, seems to think that us dumb patients need him to figure it all out for us…

You can find my publications on PubMed. Further, I meant that it is impossible for the average patient to read the methods and experiments in an academic publication and judge whether it is a reputable publication or real data. I know this because I failed myself when trying to judge treatments for my father and had to attain a PhD to fix it. As I do not have an MD and don’t treat patients, I don’t financially gain when patients are treated in the trial. My position here is as an educator to physicians on cell use and protocols, which I have the background to support. You can read my publications in the Biology of Bone and Marrow Transplantation and Blood. I further established a 501(c)3 to treat these patients at no cost, but no longer find it feasible to run the trial.

Duncan, it’d help if you clarified a few things. I have a few questions below.

In your clinicaltrials.gov listing (https://clinicaltrials.gov/ct2/show/NCT02216630) it seems to indicate that you sent patients to clinics in as many as 5 different clinic locations across the US and those patients had to pay to get the experimental therapy, but in your comment here you said you didn’t financially gain. Who did the patients pay then? And are you saying there was zero benefit to you of any kind from this whole thing?

Did you prepare each patient’s MSCs at Kimera and then the patients got those MSCs at those other clinic locations or do the separate clinics themselves prepare the patient MSCs? If it is the latter, what was your role?

Each of these clinics is my client for their regenerative medicine needs and pays me to train them generally in cell handling, which comes with access to the IRB, but the patient pays the clinic. These clinics may or may not use closed kits I produce, or they may use their own hoods. They may decide to lower the fee or not charge at all. I am not made aware of who was enrolled until I request the data at the end of the year. All clinics are instructed to provide the vitalograph COPD-6 spirometer. They often treat many different therapies, as you usually note, and may use my purified amniotic fluid (361 product) or kits for those treatments. Throughout the day, I may have up to four phone calls from one physician asking me everything from what protocols are working for hair restoration to what may work for OA or chronic pelvic pain to why PRP causes inflammation. I travel throughout the country speaking at and attending regen med and biopharmaceutical conferences and recount that information to these clinics. In the future, I see combined off the shelf FDA approved exosome based supplements to SVF treatment as a method to improve these outcomes and am working towards that IND submission in the next few months. In fact the lead PI, epidemiologists and I are meeting Aug. 1 towards that goal to prepare to request a pre pre IND meeting. Our lab is ISO:9001 certified, our hoods are ISO 5, the rooms are ISO 7. I think with a proper framework the quality of clinic based regen medicine can be raised. It has to be and a number of serious groups are trying to get to that point.

Sir, the simple question remains: have the facilities, personnel and Quality Systems used to produce clinical grade material been FDA inspected for compliance cGMP requirements? It is a yes or no proposition. Being in “compliance” with ISO guidance is not the issue. In order to manufacture or produce material, compounds, biological matter intended for intravenous injection into human subjects you legally, materially and ethically required to have the consent of the US FDA to do so. Do you have this consent or not?

I would argue that the maximum standard a clinic should be held to would be a tissue facility, and thus, AATB certification would be the path forward for clinics. That is something that could actually be accomplished.

The FDA would disagree with you.
For storing biopsies and research use, AATB and ISO certification is fine. But if it’s used to make material for IV injection or any form of claimed therapeutic benefit, including human or animal clinical trials or material used for diagnostic work, the rules for tissue banking are entirely different and must comply with all cGMP FDA regulations.

cGMP regulations apply to any material injected into humans, including Phase 1 clinical trials. So, this implies their facility has been inspected and approved by FDA to produce material for clinical trials, they have SOPs based upon validated methods for both production and testing. It is important to establish that whatever is used for Clinical trials can be reproducibly produced commercially – in other words, can meet your “label claims.”

Their web site appears to be more like a Travel agency for Medical Tourism than a medical research facility.

I agree with this. This is my point. I do not have a clinic and never did, I am a PhD scientist that helps MD’s improve their protocols, thus the IRB, and thus the SOP and sterility measures that I give them to improve their outcomes. It should be further noted that each participant received a vitalograph spirometer to track their progression, however, lack of patient compliance, both with reporting and not smoking, is the outcome I found and why I’ve diverted to my own cGMP lab to produce the IND supported therapies that Dr. Knoepfler prefers. That does not mean the world of clinical stem cell transplantation should be halted because of one bad outcome by someone that did not have the background to be teaching others. There should be a standard such as is required to teach at a University level in this state. Bioheart did not meet that criteria to be teaching.

I DON’T SEE WHY WHEN I FILE AN IND FOR ADIPOSE SVF FOR TREATING APLASTIC ANEMIA I NEED TO DO animal tox studies BUT WHEN OTHERS TREAT PATIENTS in USA and charge money the FDA doesn’t do anything to stop them

The exchange in commentary here is worth noting as an example of community engagement, yes rare, which Paul has been looking to foster amongst the diverse stakeholders in the sector. It’s in everyone’s best interest to actively participate and not just read.

This forum is an opportunity for communication between the parties to contribute, debate and clarify.

May I make a suggestion? Rather than threatening lawsuits, why don’t those of you who disagree with a publication respond on the publication’s website, or perhaps ask the editor for a chance to make the case for the critiqued therapy. Duncan, you are articulate and it would be a benefit for all if you would publish your own perspective.

I regret that I said I would sue UM. Bruce Blazar of UM is one of my heroes and a collaborator of my mentor. In fact, I had been rebuked for the study a year earlier than Leigh’s publication by my mentor. I kept the study open because I had begun a relationship with a 30 year MD/PHD surgeon from Yale that I thought could actually produce the data I was looking for. In fact, I do have a small amount of data and it is very insightful. I did complain to the publication but I doubt that is going to go anywhere. I don’t think Leigh did a good job and I don’t appreciate being spotlighted here. This press will be detrimental to my work, I am not a ‘stem cell clinic’ and I think the involved parties should be more prudent before throwing life long scientists out into this type of scrutiny.

Duncan,
I have a few more questions in trying to understand how this all unfolded.
1. I don’t know if you are OK sharing this, but can you say why you were “rebuked” as you put it by the mentor?
2. Although you’ve now said that your business is not itself directly a “stem cell clinic”, did you have any concerns that by selling experimental materials including biologics to a number of clinics for which patients then had to pay, that that might be unfair to the patients? Traditionally clinical trials do not charge participants.
3. Can you comment on the larger arena here of around 600 clinics in the US selling a whole range of stem cells and related products for many different marketed conditions?